The Pacific Northwest Udall Center (PANUC) is a collaborative enterprise among physicians and scientists at Oregon Health &Science University and the University of Washington that focuses considerable experience and expertise on cognitive impairment, a relatively poorly understood but devastating consequence that is common in patients afflicted with Parkinson's disease (PD). This proposed new Udall Center would be the only one in Oregon or the WWAMl region;WWAMI is an acronym for the cooperative arrangement among states in Pacific Northwest for which the University of Washington is the only medical school and academic medical center: Washington, Wyoming, Alaska, Montana, and Idaho. Thus, PANUC would cOver an area greater than one-fourth of the entire U.S.A. where more than 13 million Americans live. PANUC will achieve several goals of the NIH and NINDS. PANUC is: eminently patient-oriented, focused on a common non-motor feature of PD that is relatively poorly understood, organized into highly inter-related cores and projects that will promote exchange of new knowledge among clinical, translational, and basic research, anxious to contribute fully to the PD Data Organizing Center (PD-DOC) and the Coriell Institute for submission to the NINDS Human Genefics Repository, and composed of investigators who have a longstanding track record of highly collaborative productivity despite being at two institutions. Our mission is twofold. First, PANUC will serve PD patients, along with their caregivers and health care providers. We will provide improved education and clinical care, as well as offer new opportunities to participate in clinical research. Second, PANUC will discover and investigate the mechanisms that underlie cognitive impairment in PD using an array of cutting-edge technologies from accomplished and collaborative laboratories, generating novel resources for the community of scientists focused on PD, and identifying potential targets for future therapeutic development. PUBLIC HEALTH RELEVANCE: PANUC has a three-fold mission: (i) Serve patients with Parkinson disease (PD), along with their caregivers and health care providers, (ii) Investigate and elucidate mechanisms that underlie cognitive impairment (Cl) in PD using an array of cutting-edge technologies from accomplished laboratories, identifying targets for future therapeutic development, and (iii) Create new knowledge and generate novel resources for clinical, translational, and basic research to be shared with the community of scientists investigating Cl in PD. PROJECT 1 Principal Investigator: Dr.Richard Palmiter Title: Functional and Anatomical Analysis of Dopaminergic Projections that Mediate Cognition Description (provided by applicant): The goal of this project is to use a combination of genetically engineered mice and virus-mediated gene transfer in conjunction with mouse behavioral tests of learning and memory to identify the neural circuits that may underlie the cognitive decline in PD patients. We will develop two novel transgenic mouse lines that will allow us either to block genetically the production of dopamine in discrete dopaminergic projection regions by viral-mediated recombination of the tyrosine hydroxylase gene or to ablate completely dopamine neurons. We will determine whether the loss of dopamine signaling (by inactivation of tyrosine hydroxylase) or dopamine neuron death (by action pf diphtheria toxin) leads to cognitive impairment and morphological changes within the striatum and/or prefrontal cortex (in conjunction with project 2). Public Health Relevance: Parkinson's disease (PD) is caused by dopamine neuron cell death, but it is unclear if PD-related cognitive impairment is due to the loss of dopamine signaling, or to the secondary effects of dopamine neuron degeneration. We will develop 2 novel mouse models of PD to distinguish between the effects of loss of dopamine signaling and dopamine neuron degeneration on cognifive abilities.